Project Summary/Abstract Preeclampsia is a complication of pregnancy characterized by hypertension (HTN-Preg) and intrauterine growth restriction (IUGR), with unclear mechanism and limited remedies. We and others have shown that: reduction in uterine perfusion pressure (RUPP) and infusion of sFlt-1 or TNF? in pregnant (Preg) rats reduce vascular relaxation and increase vasoconstriction (VC) and BP; however, the vascular and uterine targets are unclear. Normal pregnancy involves extensive uteroplacental and vascular remodeling, and matrix metalloproteinases (MMPs) and related A Disintegrin And Metalloprotease (ADAM) family maintain adequate tissue remodeling. We have found decreases in uteroplacental and vascular MMP-2 and -9, and increases in MMP-1 and -7 in RUPP, and sFlt-1 and TNF? infused Preg rats. We have also discovered that MMPs not only degrade extracellular matrix (ECM) proteins, but also affect vascular function via effects on the Endothelium, Vascular smooth muscle (VSM) and ECM (EVE), such that MMP-2 and -9 are vasodilators (VD) while MMP-1 and -7 are vasoconstrictors (VC). Also, in search for the upstream mechanisms that trigger the changes in MMPs, our data suggest that ADAM-17, a sheddase and TNF? converting enzyme, is increased in RUPP rats, and infusion of ADAM-17 causes MMP imbalance, and increases circulating TNF? and sFlt-1, VC and BP in Preg rats. These new findings led us to the novel hypothesis that disruption of VD/VC MMP balance is a major mechanism of impaired EVE-dependent vascular pathways and HTN-Preg. Increased ADAM-17 activity triggers disruption of MMP balance. Consequently, correcting MMP imbalance by upregulating VD MMP-2 and -9 or downregulating VC MMP-1 and -7, or reducing the upstream ADAM-17 activity should improve EVE- dependent vascular pathways and HTN-Preg. Studies will be performed on Preg rats; RUPP, sFlt-1 and TNF?- infused rat models of HTN-Preg; Preg rats infused with ADAM-17, MMP-1 or -7, or treated with MMP-2 and -9 inhibitors, neutralizing antibody or siRNA; and MMP-2 and -9 deficient mice. Mechanistic studies at the whole animal, uteroplacental, microvascular and molecular levels will provide in-depth analysis of the mechanisms linking ADAM-17 and MMP imbalance to impaired EVE-dependent vascular pathways and HTN-Preg. The specific aims are to test the hypotheses that: 1) Disruption of VD/VC MMP balance during pregnancy is sufficient to impair EVE-dependent vascular pathways and cause HTN-Preg. 2) Increased ADAM-17 activity is an upstream mechanism that triggers disruption of VD/VC MMP balance, leading to impaired EVE-dependent vascular pathways and HTN-Preg. 3) Interventional correction of MMP imbalance and ADAM-17 activity is a central target to improve EVE-dependent vascular pathways and BP in HTN-Preg. These studies should provide a better understanding of the role of MMP imbalance and ADAM-17 in HTN-Preg, and highlight the potential usefulness of correcting MMP imbalance and ADAM-17 activity in the management of preeclampsia.